5-Oxa phenyl- and phenoxy-substituted prostaglandin A1 analogs

ABSTRACT

5-Oxa phenyl- and phenoxy-substituted prostaglandin-type compounds and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer by inhibition of gastric secretion, reduction of blood pressure, and increase of blood flow.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 524,549, filed Nov. 18,1974, now abandoned, which is a divisional of my co-pending applicationSer. No. 361,990 filed May 21, 1973 now issued as U.S. Pat. No.3,864,387.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter, to novel methodsfor producing those, and to novel chemical intermediates useful in thoseprocesses. Particularly, this invention relates to certain novel analogsof prostaglandins E₁, F₁.sub.α, F₁.sub.β, A₁, and B₁ in which the C-5methylene (--CH₂) in the prostanoic acid structure is replaced by oxygen(--O--).

The essential material for this application, including the background ofthe invention, the disclosure of the invention, and the description ofthe preferred embodiments, including Preparations and Examples, isincorporated by reference from U.S. Pat. No. 3,864,387, columns 1-89inclusive, under the provisions of M.P.E.P. 608.01(p).

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel 5-oxa prostaglandinE, F, A, and B analogs. It is a further purpose to provide novel 5oxaprostaglandin analogs with a variety of substituents and degrees ofsaturation in the side chains. It is a further purpose to provide 5oxaprostaglandin analogs having the 11-deoxy ring-structure in which the11hydroxy is replaced by hydrogen. It is a further purpose to provideesters, lower alkanoates, and pharmacologically acceptable salts of saidanalogs. It is a further purpose to provide novel processes forpreparing said analogs and esters. It is still a further purpose toprovide novel intermediates useful in said processes.

The novel prostaglandin analogs of this invention each have an oxygen(--O--) in place of the methylene (--CH₂ --) moiety at the 5-position ofthe prostanoic acid formula. They are represented by the generic formula##STR1## wherein is one of the six carbocyclic moieties: ##STR2##wherein ˜ indicates alpha or beta attachment of hydroxyl to thecyclopentane ring; wherein E is --CH₂ CH₂ -- or ##STR3## wherein Q₁ is##STR4## wherein R₆ and R₇ are hydrogen or alkyl of one to 4 carbonatoms, inclusive, being the same or different; wherein R₁ is hydrogen,alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbonatoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, orphenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbonatoms, inclusive; wherein R₃ is hydrogen, alkyl of one to 4 carbonatoms, inclusive, or fluoro; wherein R₂ is hydrogen or fluoro, with theproviso that R₂ is fluoro only when R₃ is hydrogen or fluoro; wherein R₄and R₅ are hydrogen or alkyl of one to 4 carbon atoms, inclusive, beingthe same or different with the proviso that no more than one of R₃, R₄,and R₅ is alkyl; and wherein R₁₄ is ##STR5## with the proviso that R₁₄is ##STR6## only when E is ##STR7## wherein C_(g) H_(2g) is alkylene ofone to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive,in the chain between --CR₈ R₉ -- and terminal methyl; wherein R₈ and R₉are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro,being the same or different, with the proviso that R₉ is fluoro onlywhen R₈ is hydrogen or fluoro; wherein T is alkyl of one to 4 carbonatoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₁₀, whereinR₁₀ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s iszero, one, 2, or 3, with the proviso that not more than two T's areother than alkyl; and wherein Z represents an oxa atom (--O--) or C_(j)H_(2j), wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, withone to 6 carbon atoms, inclusive, between --CR₈ R₉ -- and the ring.

The presently described acids and esters of the 5-oxa prostaglandinanalogs include compounds of the following formulas which are intendedto represent the same optically form as of the naturally occurringprostaglandins. There are also included the racemic compoundsrepresented by each respective formula and the mirror image thereof.There are also included the alkanoates of two to 8 carbon atoms,inclusive and also the pharmacologically acceptable salts thereof whenR₁ is hydrogen. ##STR8##

We claim:
 1. An optically active compound of the formulaor a racemiccompound of that formula and the mirror image thereof, wherein Zrepresents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is avalence bond or alkylene of one to 9 carbon atoms, inclusive,substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms,inclusive, between --CR₈ R₉ -- and the ring; wherein T is alkyl of oneto 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or--OR₁₀, wherein R₁₀ is hydrogen or alkyl of one to 4 carbon atoms,inclusive, and s is zero, one, 2, or 3, with the proviso that not morethan two T's are other than alkyl and when s is 2 or 3 the T's areeither the same or different; wherein Q₁ is ##STR9## wherein R₆ and R₇are hydrogen or alkyl of one to 4 carbon atoms, inclusive, being thesame or different; wherein R₁ is hydrogen, alkyl of one to 12 carbonatoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkylof 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted withone, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive;wherein when Z is oxa (--O--), R₈ and R₉ are hydrogen or alkyl of one to4 carbon atoms, being the same or different, and, when Z is C_(j)H_(2j), R₈ and R₉ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatR₉ is fluoro only when R₆ is hydrogen or fluoro; wherein R₃ is hydrogen,alkyl of one to 4 carbon atoms, inclusive, or fluoro; wherein R₂ ishydrogen or fluoro, with the proviso that R₂ is fluoro only when R₃ ishydrogen or fluoro; and wherein R₄ and R₅ are hydrogen or alkyl of oneto 4 carbon atoms, inclusive, being the same or different, with theproviso that no more than one of R₃, R₄, and R₅ is alkyl; including thelower alkanoates thereof, and the pharmacologically acceptable saltsthereof when R₁ is hydrogen.
 2. A compound according to claim 1 whereinQ₁ is ##STR10##wherein R₆ and R₇ are hydrogen or alkyl of one to 4carbon atoms, inclusive, being the same or different.
 3. A compoundaccording to claim 2 wherein the sum of the carbon atoms in R₆, R₇, R₈,and R₉ taken together is not greater than
 7. 4. A compound according toclaim 3 wherein R₃, R₄, and R₅ are either hydrogen or methyl, and atleast one of R₃, R₄, and R₅ is methyl.
 5. A compound according to claim3 wherein R₂, R₃, R₄, and R₅ are hydrogen.
 6. A compound according toclaim 5 wherein R₆, R₇, R₈, and R₉ are either hydrogen or methyl, and atleast one of R₆, R₇, R₈, and R₉ is methyl.
 7. A compound according toclaim 6 wherein R₆ is methyl.
 8. A compound according to claim 6 whereinR₇ is methyl.
 9. A compound according to claim 6 wherein one or both ofR₈ and R₉ is methyl.
 10. A compound according to claim 5 wherein R₆, R₇,R₈, and R₉ are hydrogen.
 11. A compound according to claim 10 wherein Zis oxo (--O--).
 12. 5-Oxa-16-phenoxy-17,18,19,20-tetranor-PGA₁, methylester, a compound according to claim
 11. 13. A compound according toclaim 10 wherein Z is methylene.
 14. An optically active compoundaccording to claim
 13. 15. A compound according to claim 14 wherein R₁is alkyl of one to 12 carbon atoms, inclusive. 16.5-Oxa-17-phenyl-18,19,20-trinor-PGA₁, methyl ester, a compound accordingto claim
 15. 17. A compound according to claim 14 wherein R₁ ishydrogen.